Topical acne vulgaris medication with a sunscreen

ABSTRACT

Increased compliance in the use of topical sunscreens is obtained by combining a topical sunscreen agent in a formulation containing an antibacterial medication such as azelaic acid or an antibiotic.

This application is a divisional application of pending U.S. patentapplication Ser. No. 11/393,981, filed on Mar. 29, 2006 now U.S. Pat.No. 7,252,816.

FIELD OF THE INVENTION

The invention pertains to the field of topically applied medicationsused to treat acne vulgaris.

BACKGROUND OF THE INVENTION

It is well established that both acute and chronic sun exposure hasgeneral detrimental effects to the skin over time. Intervention with theuse of sunscreens and sunblocks at a young age is advocated bydermatologists around the world. However compliance is minimal.Avoidance of sun exposure early in life is thought to be particularlyimportant because the carcinogenic effects of the sun are cumulative andare manifested years after the exposure. For children, compliance isdependent primarily on the diligence of the parents. During the teenageyears responsibility shifts to the individual, yet teenagers arenotoriously noncompliant with the use of sunscreens. In fact the “sunexposed appearance” is regarded as desirable among teenagers generally.Sunscreen use for outdoor activities by adolescents and young adults ishighly important for healthy skin, i.e., to minimize the risk ofdeveloping skin cancers and to reduce the premature signs of skin agingover time. Therefore, the public health need is great to improve and tofacilitate the regular use of sunscreens among adolescents and youngadults. It is particularly important to protect the facial area whichreceives intense and repeated sun exposure.

Recent studies published by the American Academy of Dermatologyhighlight the lack of compliance of young adults and teenagers in theuse of sunscreens. In a study entitled “New American Academy ofDermatology Survey Finds People Aware of the Dangers of the Sun, But SunProtection Not Necessarily Practiced,” Am. Acad. Dermatol. (Apr. 29,2003), it was reported that, although 79% of surveyed parents andgrandparents apply sunscreen to children when they play outdoors, thisnumber drops to only 34% for independent young people under the age of25. In another study entitled, “New Study Finds High School Students GetEnough UV Exposure on an Average Day to Cause Sunburn”, Am. Acad.Dermatol. (Apr. 24, 2002), it was reported that, when high schoolstudents between the ages of 12 and 17 were provided with Ultraviolet Bdosimeters to wear on their wrists, UVB exposure that occurred duringregular daily activities was sufficient to cause sunburn in somestudents. Moreover, even though UVB exposure was less on cloudy days,the amount of UVB exposure on these days was higher than expected and80% of the sun's UV rays pass through the clouds. The study alsoestimated that almost 80% of a person's lifetime sun exposure occursbefore the age of 18 Therefore, reducing the exposure of teenagers toharmful rays of the sun is extremely important. In another studyentitled “Skin Cancer Awareness and Sun Protection Behaviors in CollegeStudents”, J. Acad. Dermatol., Abstract P1321, page P107 (March 2005),it was reported that the majority of college students do not usesunscreen on a regular basis. In fact, fully 81% of college studentssurveyed reported that they never, rarely, or only sometimes usesunscreen.

In a recent article, Kullavanijaya, P, and Lim, HW, J. Am. Acad.Dermatol., 52:937-958 (June 2005), incorporated herein by reference,review the various types of ultraviolet radiation, the harms that theserays can cause upon exposure to skin, and various types of sunprotective agents that are applied to protect the skin. As disclosed byKullavanijaya and Lim, most presently available sunscreen agents areeffective primarily in blocking UVB rays and are photolabile, that isthey are degraded upon exposure to ultraviolet radiation. Many of theavailable sunscreens also induce adverse effects such as irritation,allergic contact reactions, photoallergy, and phototoxic effects.

Newer sunscreen agents such as benzene1,4-di(3-methylidene-10-camphosulfonic acid (MEXORYL SX®, L'Oreal,Clichy, France) (described in U.S. Pat. No. 4,585,597, incorporatedherein by reference), drometriazole trisiloxane (MEXORYL XL®, L'Oreal,Clichy, France) (described in U.S. Pat. No. 4,585,597),methylene-bis-benzotriazoyl tetramethylbutylphenol (bisoctrizole,TINOSORB M®, Ciba Specialty Chemicals, Basel, Switzerland) (described inU.S. Pat. Nos. 5,869,030; 5,980,872; and 6,521,217, each of which isincorporated herein by reference), and bis-ethylhexyloxyphenolmethoxyphenol triazine (anisotriazine, TINOSORB S®, Ciba SpecialtyChemicals) (described in U.S. Pat. Nos. 5,869,030; 5,980,872; and6,521,217), as well as the inorganic sunscreen agents titanium oxide(TiO₂) and zinc oxide (ZnO) are reported by Kullavanijaya and Lim to notshare these disadvantages. These agents are broad spectrum UV absorbers,are photostable, and have not been found to cause the adverse effectsassociated with other sunscreen agents.

Acne vulgaris, often referred to as “acne”, is a condition that isdistinct from and is not related to acne rosacea. Acne vulgaris is adisorder of the pilosebaceous follicle. Common features of acne vulgarisinclude increased sebum production, follicular keratinization,colonization by Propionibacterium acnes, and localized inflammation.

Treatment for acne vulgaris is typically with one or more of a retinoid,such as tretinoin or isotretinoin, an antibiotic, such as clindamycin orerythromycin, or other medication such as azelaic acid, a sulfonamide,and antibacterials such as benzoyl peroxide. Retinoid compounds increasethe sensitivity of skin to the sun and are often inactivated byultraviolet light. Therefore, retinoid products are recommended to beused at night or together with a sunscreen. Sulfonamides likewiseincrease the sensitivity of skin to the sun and, therefore, may becombined with a sunscreen. Benzoyl peroxide is highly reactive anddegrades upon exposure to the sun. Therefore, benzoyl peroxide may becombined with a physical sunscreen to inhibit this sun-induceddegradation. Such problems have not been associated with the use ofantibiotics, such as those of the lincomycin family, or with azelaicacid or salicylic acid.

Acne rosacea, often referred to simply as rosacea, is a separatedistinct dermatological disorder, which is a chronic inflammatory skindisorder characterized by enhanced epidermal proliferation leading toerythema, typically with flushing, scaling, and thickening of the skin.Rosacea is often exacerbated by exposure to the sun. Therefore,treatment of rosacea often includes the use of sunscreens. In contrastto rosacea, acne vulgaris primarily affects young people, during theteenage years and sunscreens have no known beneficial role in treatingacne vulgaris. In fact many sunscreens have been reported to becomedogenic, that is they have the potential to induce comedones whichare the primary lesions of acne vulgaris.

The present invention is directed to methods of treating and preventingor inhibiting recurrences of acne vulgaris and addresses the significantneed for increasing the compliance in the application of topicalsunscreens in individuals suffering from or at risk of developing acnevulgaris, primarily teenagers and other adolescents and young adults. Inthis way, chronic effects of overexposure to harmful rays of the sun,such as skin cancers, can be greatly reduced.

DESCRIPTION OF THE INVENTION

The present invention addresses a problem that has not been adequatelyaddressed in the prior art and provides a solution to that problem thatis distinct from the prior art. The present invention, in its severalembodiments, provides a solution to the problem of how to increasecompliance in the use of sunscreens, primarily in young people whotypically receive a high proportion of their lifetime sun exposurebefore the age of 20 and who are notoriously non-compliant in the use ofsunscreens, especially to the facial areas.

Although the prior art discloses compositions containing certainantibacterial compounds (erythromycin or sulfacetamide) in combinationwith a sunscreen, the sunscreens in these products are provided eitherto reduce phototoxic effects of an anti-acne medication or to reduce thesun-induced degradation of the medication. The sunscreens in thesecompositions were not directed to the problem of reducing facial sunexposure to the individual, except as mentioned to reduce harmfuleffects of the antibacterial compounds present in the composition.Accordingly, because the prior art is not concerned with the problem ofprotection from daily sun exposure in the adolescent and young adultpopulations, the prior art does not disclose sunscreens that arephotostable to be combined with these antibacterial compounds.

In contrast, the present invention addresses the problem of lack ofcompliance in the use of sunscreens, which sunscreens are utilized toprotect an individual from the harmful effects due to exposure to thesun. Therefore, certain embodiments utilize a photostable sunscreenagent, as described in more detail below.

The invention, in one embodiment, is a composition for the topicaltreatment of acne vulgaris. According to this embodiment of theinvention, the composition contains one or more sunscreen agents, suchas a photostable broad spectrum sunscreen agent, and one or moreanti-acne vulgaris chemical agents selected from an antibiotic, like anantibiotic of the lincomycin family, such as lincomycin hydrochloride,lincomycin phosphate, clindamycin phosphate, and clindamycinhydrochloride, azelaic acid, and salicylic acid. Typically, theanti-acne vulgaris agent and the sunscreen agent are dissolved orsuspended in a vehicle, such as water, alcohol, or propylene glycol. Thecomposition of the invention is preferably used in single daily ormultiple times daily application to the facial area. Preferably,application is once daily, preferably in the morning. The form of thedrug product may be a gel, spray, foam, lotion or other dosage form thatis cosmetically acceptable for use on the face and which is easilyspreadable on the skin. It is preferred to apply the composition of theinvention uniformly to all of the acne prone and sun exposed facial andneck areas to optimally treat acne and to reduce the incidence andseverity of sunburn and chronic skin damage from solar radiation. Thecomposition of the invention should be spread uniformly on the skin,such as by using the hands and fingers, to completely cover the intendedareas of treatment. If the acne medication is used twice daily, thepreferred times of application are morning and midday, that is duringthe hours of sunlight.

The invention is not intended to be used for “spot treatment” ofindividual acne lesions. Rather, the method of treatment of theinvention involves application to broad areas of the face and neck.

In a preferred embodiment, the composition further contains anantioxidant. It has been unexpectedly discovered that combining anantioxidant in a composition containing an antibiotic of the lincomycinfamily such as clindamycin, and a sunscreen agent, such as a photostablebroad spectrum sunscreen like zinc oxide, titanium oxide, or Tinosorb Mprovides a more stable composition with reduced degradation of theclindamycin during storage. A preferred antioxidant is sodiumthiosulfate. Other suitable antioxidants include butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodiummetabisulfite, ascorbic acid, ascorbyl palmitate, thiourea,acetylcysteine, dithiothreitol, cysteine hydrochloride, propyl gallate,and the tocopherols.

The invention, in another embodiment, is a method for topically treatingacne vulgaris. Concomitantly, the skin is protected from exposure to thesun. According to this embodiment of the invention, a compositioncontaining one or more sunscreen agents, such as a photostable broadspectrum sunscreen agent, and one or more anti-acne chemical agents,such as azelaic acid or salicylic acid, or an antibiotic like a memberof the lincomycin family, such as lincomycin hydrochloride, lincomycinphosphate, clindamycin phosphate, and clindamycin hydrochloride, isapplied to the skin of a subject suffering from or at risk of developingskin lesions due to acne vulgaris.

The invention, in another embodiment, is a method for increasing thecompliance by individuals such as teenagers and young adults, that isindividuals between the ages of 10 and 25, such as between the ages of13 and 20, and especially those individuals less than 20 years old, inthe application of sunscreen, especially to the skin of the face.Adolescents and young adults are often susceptible to, or are sufferingfrom, acne vulgaris and are highly motivated to apply medicationfaithfully to treat or to combat this condition. By combining asunscreen, such as a photostable broad spectrum sunscreen agent, in aformulation containing an anti-acne vulgaris medication, such as azelaicacid or salicylic acid, or an antibiotic like an antibiotic of thelincomycin family, such as lincomycin hydrochloride, lincomycinphosphate, clindamycin phosphate, and clindamycin hydrochloride, suchindividuals will be concomitantly applying a sunscreen, even though suchindividuals would be less likely do so if the sunscreen were notcombined with the anti-acne medication.

As used herein, the term “sunblock” refers to physical sunscreeningagents that block exposure of the skin to ultraviolet light. As usedherein, the term “sunscreen” or “sunscreen agent” refers to either aphysical sunscreen (a sunblocking agent) or a chemical sunscreen. Thus,the term “sunscreen” is broader than the term “sunblock” and encompassesthe term “sunblock”. As used herein, the term “sunscreen formulation”refers to a formulation that contains a sunscreen and additionalcomponents.

As used herein, the terms “photostable sunscreen agent” and “photostablesunscreen formulations” refer to a sunscreen agent or to a formulationcontaining a sunscreen agent which agent or formulation absorbsultraviolet radiation at a level that is 50% or higher of the UVabsorbance of the agent or formulation prior to irradiation followingexposure of a 0.5 ml sample per square centimeter (cm²) in a quartzpetri dish of a formulation containing a sunscreen agent to irradiationof 200 watt-h/m² from a xenon lamp source that correlates to the fullspectrum of outdoor sunlight as specified in the International Standardfor Outdoor Daylight D65. The photostable sunscreen formulation maycontain a sunscreen agent which is stable as it exists within theformulation but which is unstable inherently. Thus, a formulation isconsidered to be a photostable sunscreen formulation if it contains asunscreen that is inherently unstable but is photostable, as definedabove, when combined with one or more components present in theformulation.

Sunscreen agents and sunscreen formulations that are suitable for thepresent invention are photostable as defined above. It is preferred,however, that the photostable sunscreen agents and photostable sunscreenformulations that are used in accordance with the invention be even morestable than that defined above. In a preferred embodiment, the sunscreenagent or sunscreen formulation absorbs ultraviolet radiation at a levelthat is 75% or higher following the exposure to the xenon lamp source.This level of photostability is referred to herein as “75%photostability.” It is most preferred that the sunscreen agents orsunscreen formulations absorb ultraviolet radiation at a level that is90% or higher following exposure to the xenon lamp source, referred toherein as “90% photostability.”

As used herein, a “broad spectrum sunscreen agent” is a chemicalcompound that absorbs or blocks exposure of both UVB (280 to 320 nm) andUVA (320 to 400 nm). A chemical compound is a broad spectrum sunscreenagent as defined herein if can be formulated to produce an SPF (SunProtection Factor) of 5 to 10, as determined in accordance with theTesting Procedure specified in 21 C.F.R. Sec. 352.70-352.77 (SubpartD-Testing Procedures), and has a UV-A/UV-B ratio at least 0.75, or ifcan be formulated to produce an SPF of >10 to 15 and has a UV-A/UV-Bratio at least 0.50, or if it can be formulated to produce an SPF of >15to 25 and has a UV-A/UV-B ratio at least 0.33, or if it can beformulated to produce an SPF of >25 and has a UV-A/UV-B ratio at least0.25. The UV-A/UV-B ratio is calculated as the ratio between the areasdefined by the UV-A and UV-B extinction capacity, as shown in thefollowing formula wherein A=absorbance and λ=wavelength:

$\frac{\int_{320}^{400}{{A(\lambda)}\ {{\mathbb{d}\lambda}/{\int_{320}^{400}\ {\mathbb{d}\lambda}}}}}{\int_{290}^{320}{{A(\lambda)}\ {{\mathbb{d}\lambda}/{\int_{290}^{320}\ {\mathbb{d}\lambda}}}}}$

As used herein, “a broad spectrum sunscreen formulation” is aformulation that absorbs or blocks exposure of both UVB and UVAradiation according to the definition above for a broad spectrumsunscreen agent. Such a formulation may contain one or more broadspectrum sunscreen agents or may contain a multiplicity of sunscreenagents that individually are not broad spectrum agents but, whencombined in a formulation, provide a broad spectrum sunscreen function.

Examples of sunscreen agents that are broad spectrum photostablesunscreen agents include inorganic sunscreen agents such as titaniumoxide and zinc oxide and tautomeric sunscreen agent compounds such asMEXORYL SX®, MEXORYL XL®, bisoctrizole, and anisotriazine.

As a way to improve the sunscreen usage of teenagers and young adults,this invention embodies a sunscreen, such as a photostable broadspectrum sunscreen, as a second active component along with a topicalacne medication. Adolescents and young adults are very commonlyafflicted with acne vulgaris and are generally motivated to usepreventative topical medications to control acne and maintain theirappearance in a positive way. Acne afflicts the face and neck areasprimarily and these areas are also the skin areas with the greatestdegree of chronic sun exposure.

Additionally patients being treated for acne are at additional risksfrom sun exposure due to the detrimental effect of sun exposure incombination with commonly used acne medications, both topical and oral.Thus, this invention piggybacks the use of a sunscreen, which is notperceived by teenagers and young adults to be important, on the use of atopical acne medication, which is perceived to be important. Anysunscreen or sun block combined with an antibacterial medicationembodies this invention in its broad conception.

In accordance with a preferred embodiment of the invention, thesunscreen is a broad spectrum sunscreen agent or combination of agents.The broad spectrum sunscreen may an inorganic sunscreen agent, such asone or more of zinc oxide (ZnO), titanium oxide (TiO₂), or ferric oxide(Fe₂O₃), which may be in a micronized form. These sunscreen areeffective against exposure to UVA (ultraviolet-A) and UVB(ultraviolet-B) light. Alternatively, the sunscreen may be an organicsunscreening agent. An example of an organic sunscreen that is suitablefor the invention is a benzotriazole sunscreen, such as methylenebis-benzotriazolyl tetramethylbutyl phenol (MBBT), marketed under thetrade name TINOSORB® M (Ciba Specialty Chemicals, Inc., Basel,Switzerland). Other suitable but less preferred organic sunscreeningagents include para-aminobenzoic acid (PABA) and derivatives,anthranilates, benzophenones, cinnamates includingoctylmethoxycinnamate, and salicylates. Other preferred organicsunscreen agents are a camphor derivative such as terephthalylidenedicamphor sulfonic acid, marketed under the trade name MEXORYL® SX(L'Oreal USA, New York N.Y.), and ibenzoylmethanes such as butylmethoxydibenzoylmethane (PARSOL® 1789, AVOBENZONE®, Givaudon-RoureCorporation, Totowa, N.J.). A less preferred organic broad spectrumsunscreen agent is oxybenzone, also known as benzophenone, because ofrecent findings that oxybenzone is associated with a high incidence ofskin irritation and is absorbed through the skin into the systemiccirculation. The choice and concentration of sunscreens should be madein such a way to achieve a sun protection factor (SPF) of at least about5, preferably at least about 10, and most preferably about 15 or more.

It is also preferred that the sunscreen agent or that the formulation ofthe invention containing a sunscreen agent be non-comedogenic. Asunscreen agent or formulation may be determined to be non-comedogenicby the following test.

The comedogenicity test is conducted using semi-occlusive patches on thebacks of 20 human volunteers. Subjects exhibiting follicularhyperkeratosis (microcomedones) with a grade 0.5 to 1.0 are suitable forinclusion in the study. Microcomedones are graded on a scale of 0 to 3with 0=none, 0.5=slight (tiny horny masses), 1=mild (small horny massesinvolving at least half of the follicles), 2=moderate (moderately sizedhorny masses over most of the field) and 3=severe (large globoidmicrocomedones over the entire field) based on follicular biopsy samplesfrom the test area of the back. (Mills, Ohio, The follicular biopsy. InSerup J, Jemec GBE (eds) Handbook of Non-Invasive Methods and the Skin.CRC Press, Baca Raton, La. (1995)). Follicular biopsies are conducted atbaseline (up to 45 days prior to study start) and at study end. If asubject has an irritation score of more than 1 at study end, a restperiod is given until the initiation score is 1 or less, at which timethe final follicular biopsy is performed.

Semi-occlusive patches with 0.1 ml of test product are applied 3 timesper week and left in place for 48-72 hours before reapplication to thesame site for a 4 week period. Assessments of irritation are made on a6-point scale with 0=no sign of irritation, 0.5=barely perceptibleredness, 1=slight redness, 2=noticeable erythema with slightinfiltration, 3=erythema with marked edema, or 4=erythema with edema andblistering. A negative control which is a non-occlusive patch withoutany test material is applied. The average microdomedone scores for thenegative control and the test material are calculated separately bydividing the total of the score by the number of test subjects. A testmaterial is judged to be non-comedogenic if the average score is notmore than 0.5 units higher than the negative control.

The acne medication that is useful in the present invention is azelaicacid or salicylic acid, or an antibiotic. The acne medication of thepresent invention is preferably one that is photostable and that doesnot increase sensitivity of the skin to sun exposure. As used herein,the terms “photostable” in reference to the acne medication means thatthe acne medication retains at least 75% of its activity followingexposure of the medication in a 0.5 ml sample per square centimeter(cm²) in a quartz petri dish of a formulation containing the acnemedication agent to irradiation of 200 watt-h/m² from a xenon lampsource that correlates to the full spectrum of outdoor sunlight asspecified in the International Standard for Outdoor Daylight D65.

Preferred antibiotics include macrolide antibiotic includingerythromycin, azithromycin, clarithromycin, tilmicosin, and tylosin, andlincomycin-type antibiotics such as clindamycin hydrochloride,clindamycin phosphate, lincomycin phosphate, or lincomycinhydrochloride. Additional topical anti-acne active ingredients may becontained in the composition of the invention if desired in combinationwith the salicylic acid, azelaic acid, or antibacterial compound. Suchadditional topical anti-acne active ingredients include but are notlimited to one or more additional antibiotics, salicylic acid, azelaicacid, niacinamide, urea peroxide, and retinoids such as tretinoin,adapalene and tazarotene.

Preferably, the topical acne medication is photostable and does notincrease the incidence of adverse reactions to sun exposure, such asoccurs commonly with sulfonamides and tetracycline. In topicalcompositions containing such medications, such as ROSAC® Cream (StiefelLaboratories, Inc., Coral Gables, Fla.), a sunscreen is included toprevent the deleterious effects of the sun's radiation in combinationwith a sulfonamide. This is in contrast to the present invention inwhich a sunscreen is utilized for its effect in preventing damage to anindividual caused by exposure to the sun and in which the anti-acnemedication in the composition is not degraded by the sun and does notinduce adverse effects to an individual when exposed to the sun.Therefore, medications that degrade due to sun exposure or that resultin injury to an individual upon exposure to the sun, such assulfonamides and tetracycline, are expressly excluded from the scope ofthe present invention.

Additionally, certain skin care compounds, such as benzoyl peroxide, arereactive and degrade due to exposure to sun. For that reason, thesecompounds may be combined in a composition with a sun filter. SeeBouillon, et al, U.S. Pat. No. 4,671,956. Compositions containingbenzoyl peroxide are expressly excluded from the scope of the presentinvention.

The amount and concentration of sunscreen in the composition will varydepending on the particular sunscreen present but is an amount andconcentration which is effective to protect an individual from the UVradiation. Similarly, the amount and concentration of the anti-acnemedication will vary depending on the particular anti-acne medication inthe composition but is an amount that is effective to treat, prevent, orreduce the symptoms of acne vulgaris.

For an optimally effective sunscreen formulation, two or more activesunscreen ingredients may be combined in a composition in order toattain both the breadth of sunscreen protection (UVB and UVA) as well asto achieve sufficient SPF. There are a great many sunscreen ingredientslisted in the FDA's OTC monograph of approved sunscreen activeingredients in addition to the sunscreens that are described herein.However, as described above, it is preferred that the composition of theinvention contain a broad spectrum sunscreen effective against both UVAand UVB. It is further preferred that the sunscreen is photostable.

Further, there are a multitude of anti-acne ingredients that may be usedin the topical treatment and prevention of acne. The anti-acneingredients, such as salicylic acid, azelaic acid or an antibiotic, maybe used singly in the formulation of the invention or in combinationwith one or more other anti-acne ingredients, such as those listedabove. One important factor in utilizing the compositions and methods ofthe present invention is the selection of anti-acne ingredients andsunscreen ingredients that are compatible with and that are stablewithin the selected vehicle. There can be physical and chemicalincompatibilities wherein one active ingredient adversely affectsanother or the vehicle. The present invention involves stableformulations in which each active ingredient is compatible within theformulation. This means that the formulation is physically andchemically stable, that is the physical properties of viscosity, odor,and color of the formulation remain substantially unchanged upon storagefor a period of 12 months at 25° C. and there is no more than a 10% lossof any active ingredient (sunscreen agent or anti-acne medication) whenthe formulation is stored for this period of time at this temperature.Making such formulations is described herein, and methods for themanufacture and testing of such formulations for stability are known tothose skilled in the art.

Many anti-acne medications and many sunscreens are capable of causingskin irritation. Therefore, if a potentially irritating anti-acnemedication is included in the composition of the invention, it ispreferred that a non-irritating sunscreen or one with a low irritationpotential, such as titanium dioxide, be included. Likewise, if apotentially irritating sunscreen is included in the composition, it ispreferred that the anti-acne medication in the composition not beirritating or be only mildly irritating.

An additional benefit of the invention to persons suffering from acne issun protection, and avoidance of exacerbating the condition when using aproduct based on this invention. As a result of using the combinedproduct, patients exposed to the sun may be effectively treated by theanti-acne component and be protected from sun exposure.

As previously stated, individuals in the typical acne age group isgenerally not motivated to use sunscreen products, yet are highlymotivated to use products to prevent, treat, and manage their acne. Acnepatients under the care of physicians are most commonly given multiplemedications as part of their over all treatment regimen. Often, patientcompliance is a problem in managing such patients because the youngpatients do not consider protection from the sun to be of greatimportance even though they typically place great importance on treatingtheir acne. According to the invention, the sunscreen is combined in thesame formulation as the anti-acne medication. This results in anincreased compliance for the use of sunscreen products because thepatients are motivated to use the anti-acne medication which is incombination with the sunscreen.

The formulation is preferably a semi-solid dosage form, but it may be aliquid including a spray, also. Among the most preferred semi-soliddosage forms, gels are the most preferred, followed by foams, lotions,and creams. Foams, lotions, and creams preferably have a low ratio ofoil phase, if present, to water phase. Cosmetic elegance andspreadability of the vehicle are important aspects of this invention inorder to obtain patient compliance and uniform and complete applicationof the sunscreen component to the skin.

By increasing the routine use of sunscreens by adolescents and youngadults, multiple health benefits are obtained, including:

-   -   An effective method of having adolescents regularly use        sunscreens on exposed facial areas,    -   Reduced long-term risk of skin cancer,    -   Minimization of the visible signs of skin aging,    -   Preventing the photo-exacerbation of acne that occurs with        sun-exposed acne patients, thus obtaining improved efficacy with        the anti-acne component of the combination, and    -   Establishing the habit in these young people of protecting the        skin from daily sun exposure and of being responsible for the        maintenance of healthy skin.

The invention is further illustrated in the following non-limitingexamples that show various embodiments of the invention in variousliquid and semisolid dosages forms such as gels, lotions, ointments, andcreams. The components of the various embodiments are combined together,such as by mixing, to form the composition. A more detailed procedurefor making the composition is provided in the Examples. The compositionsof the invention illustrated in the examples above may be made using theprocedures described, or by using an alternative procedure known by oneskilled in the art.

EXAMPLE 1

A gel composition of the invention may have the following components asshown in Table 1.

TABLE 1 Percent COMPONENT (by weight) Clindamycin Phosphate 1.20 OctylMethoxycinnamate 7.50 Oxybenzone 1.00 Edetate Disodium 0.05Methylparaben 0.17 Propylparaben 0.03 Sodium Docusate (85%) 1.00Propylene Glycol 10.00  Sodium Hydroxide q.s. pH ≈ 5.5 Carbopol ® 981(Noveon, Cleveland, OH) 0.60 Purified Water q.s. ad 100

The gel of Table 1 may be made using the following procedure, or analternative procedure known by one skilled in the art that is effectiveto combine the components in a uniform mixture.

Dissolve the disodium edetate in about 90% of the needed water withpropeller mixing. Then dissolve the clindamycin phosphate in the firstsolution again with propeller mixing until the drug is dissolved. Afterdissolving methylparaben and propylparaben in propylene glycol usingheat as needed up to about 80° C. and propeller mixing, add thissolution slowly while mixing to the clindamycin solution. Then dissolvethe sodium docusate in the clindamycin solution with propeller mixing.Disperse the Carbopol® in the clindamycin solution to form a uniformdispersion. After dissolving the oxybenzone in the octylmethoxycinnamate, slowly pour this sunscreen solution into the Carbopol®dispersion while mixing with a propeller mixer until uniform. Aftermaking a 1% sodium hydroxide solution, with continuous mixing add itslowly and stepwise to the Carbopol® dispersion until the designated pHis attained. Add the remaining water and mix into the gel uniformly.

EXAMPLE 2

A gel composition of the invention based on clindamycin as the anti-acneagent with Tinosorb® M and octyl methoxycinnamate as the sunscreens canbe made as follows with the components shown in Table 2.

TABLE 2 Percent COMPONENT (by weight) Clindamycin Phosphate 1.20 OctylMethoxycinnamate 5.00 Tinosorb ® M 5.00 Edetate Disodium 0.05Methylparaben 0.17 Propylparaben 0.03 Propylene Glycol 10.00  SodiumThiosulfate Pentahydrate 0.16 Sodium Hydroxide q.s. pH ≈ 5.5 Carbopol ®981 0.60 Purified Water q.s. ad 100.00

Dissolve the disodium edetate in about 90% of the needed water withpropeller mixing. Then dissolve the clindamycin phosphate in the firstsolution again with propeller mixing until the drug is dissolved. Afterdissolving methylparaben and propylparaben in propylene glycol usingheat as needed up to about 80° C. and propeller mixing, add thissolution slowly while mixing to the clindamycin solution. Then dissolvethe sodium thiosulfate and sodium docusate in the clindamycin solutionwith propeller mixing. Disperse the Carbopol® in the clindamycinsolution to form a uniform dispersion. Next add Tinosorb® M and octylmethoxycinnamate into the Carbopol® dispersion while mixing with apropeller mixer until uniform. After making a 1% sodium hydroxidesolution, with continuous mixing add it slowly and stepwise to theCarbopol® dispersion until the designated pH is attained. Add theremaining water and mix into the gel uniformly.

The resulting formulation is a cosmetically elegant, low viscosity gel.This composition of the invention has broad protection into the UVA-1and UVA-2 regions of solar irradiation in addition to the UVBprotection.

EXAMPLE 3

The composition of the invention can be made in a variety ofpharmaceutical dosage forms that are liquid or semisolid. The currentexample is a lotion formulation containing clindamycin as the anti-acneagent and two sunscreens as follows as shown in Table 3.

TABLE 3 Percent COMPONENT (by weight) Clindamycin Phosphate 1.20 OctylMethoxycinnamate 6.00 Tinosorb ® M 4.00 Edetate Disodium 0.05 SodiumThiosulfate Pentahydrate 0.10 Benzyl Alcohol 1.00 Steareth 2 0.75Steareth 21 2.25 Propylene Glycol 10.00  Cetyl Alcohol 4.00 IsopropylMyristate 6.00 Sodium Hydroxide q.s. pH ≈ 5.5 Carbopol ® 981 0.10Purified Water q.s. ad 100.00

The lotion of Table 3 may be made by first dissolving the disodiumedetate, sodium thiosulfate, propylene glycol, and benzyl alcohol in thewater with mixing with a propeller mixer. Then dissolve the clindamycinphosphate in the first solution, mixing until the drug is dissolved.Disperse the Carbopol® in the clindamycin solution to form a uniformdispersion. Next add Tinosorb® M into the Carbopol® dispersion whilemixing. After making a 1% sodium hydroxide solution, with continuousmixing add it slowly and stepwise to the Carbopol® dispersion until thedesignated pH is attained, thus completing the water phase. Make the oilphase by combining octyl methoxycinnamate, isopropyl myristate, cetylalcohol, steareth 2, and steareth 21, all of which is heated to about65° C. with mixing. Heat the water phase to about 65° C. and add the hotoil phase thereto while mixing with the propeller mixer until the lotioncools to room temperature.

EXAMPLE 4

Following is a cream formulation of the invention containing clindamycinas the anti-acne agent and two sunscreens as follows in Table 4.

TABLE 4 Percent COMPONENT (by weight) Clindamycin Phosphate 1.20 OctylMethoxycinnamate 6.00 Oxybenzone 1.00 Edetate Disodium 0.05 GlycerylMonostearate 3.00 Benzyl Alcohol 1.00 Carbopol ® 1382 (Noveon,Cleveland, OH) 0.05 Pemulen ® TR-1 (Noveon, Cleveland, OH) 0.20Propylene Glycol 10.00  Cetyl Alcohol 4.00 Isopropyl Myristate 8.00Sodium Hydroxide q.s. pH ≈ 5.5 Carbopol ® 941 (Noveon, Cleveland, OH)0.30 Purified Water q.s. ad 100.00

The cream of this example may be made by first dissolving the disodiumedetate, propylene glycol, and benzyl alcohol in the water with mixingwith a propeller mixer. Then dissolve the clindamycin phosphate in thefirst solution, mixing until the drug is dissolved. Disperse theCarbopols® and Pemulen® in the clindamycin solution to form a uniformdispersion. After making a 1% sodium hydroxide solution, with continuousmixing add it slowly and stepwise to the Carbopol® dispersion until thedesignated pH is attained, thus completing the water phase. Make the oilphase by combining octyl methoxycinnamate, oxybenzone, isopropylmyristate, cetyl alcohol, and glyceryl monostearate, all of which isheated to about 65° C. with mixing. Heat the water phase to about 65° C.and add the hot oil phase thereto while mixing with an appropriate mixeruntil the cream cools to room temperature.

EXAMPLE 5

This example of the composition of the invention is a solutionformulation containing erythromycin base as the anti-acne agent and twosunscreens as follows and as shown in Table 5.

TABLE 5 Percent COMPONENT (by weight) Erythromycin 2.00 OctylMethoxycinnamate 5.00 Tinosorb ® S 5.00 Isopropyl Myristate 1.00Propylene Glycol 15.00  Dehydrated Alcohol, USP q.s. ad 100.00

The erythromycin-sunscreen solution is made by first dissolvingerythromycin base in the alcohol with mixing. Then each of the remainingcomponents is added and dissolved in the alcohol with mixing, preferablyone component at a time.

EXAMPLE 6

A spray dosage form of the composition of the invention is made, forexample, by packaging the composition of Example 5 in a bottle fittedwith a spray pump closure that can be mechanically actuated by apatient.

EXAMPLE 7

The composition of the invention may be formulated as a gel formulationcontaining erythromycin base as the anti-acne agent and two sunscreensas follows and as shown in Table 6.

TABLE 6 Percent COMPONENT (by weight) Erythromycin 2.00 OctylMethoxycinnamate 5.00 Tinosorb ® S 5.00 Isopropyl Myristate 1.00Propylene Glycol 15.00  Hydroxypropyl Cellulose 2.00 Dehydrated Alcohol,USP q.s. ad 100.00

The erythromycin-sunscreen gel may be made by dissolving erythromycinbase in the alcohol with mixing. Then each of the following ingredientsis added and dissolved with propeller mixing, preferably one at a timeand in the following order: octyl methoxycinnamate, Tinosorb® S,isopropyl myristate, and propylene glycol. Finally, add thehydroxypropyl cellulose polymer slowly with intense mixing to dispersethe polymer followed by side-scrape and countercurrent mixing to make ahomogeneous gel.

EXAMPLE 8

The composition of the invention may be formulated as a solutionformulation containing salicylic acid as the anti-acne agent andsunscreens as follows and as shown in Table 7.

TABLE 7 Percent COMPONENT (by weight) Salicylic Acid 2.00 OctylMethoxycinnamate 3.00 Oxybenzone 1.00 Ethoxydiglycol 10.00 Polysorbate20 10.00 Cocamide DEA 5.00 Polyethylene Glycol 300 10.00 Tromethamineq.s. pH ≈ 4.5 Purified Water q.s. ad 100.00

The solution is made by mixing the ethoxydiglycol, polysorbate 20,cocamide DEA, polyethylene glycol 300 and water together, and thendissolving the salicylic acid therein. Then the pH is adjusted byincremental additions of tromethamine (as a 10% solution) to the desiredlevel. Finally the oxybenzone and octyl methoxycinnamate are added anddissolved with propeller mixing.

EXAMPLE 9

The composition of the invention may be formulated as a topicalnon-aerosol foam with salicylic acid as the active anti-acne drugsubstance. The solution from example 8 is packaged in a Plastic bottlefitted with a “foamer” pump/closure such as Airspray M3 pumpassembly/closure (Airspray International Inc., Pompano Beach, Fla.).

EXAMPLE 10

The composition of the invention may be formulated as an aerosol foam ormousse composition as follows and as shown in Table 8.

TABLE 8 Percent COMPONENT (by weight) Clindamycin Phosphate 1.20 OctylMethoxycinnamate 2.50 Tinosorb ® S 2.50 Ethoxydiglycol 5.00 Polysorbate20 2.00 Lauramine Oxide 1.0 Cetyl Alcohol 0.50 Stearyl Alcohol 0.50Propylene Glycol 10.00 Disodium Edetate 0.05 Methylparaben 0.17Propylparaben 0.03 Sodium Hydroxide q.s. pH ≈ 5.5 Purified Water q.s. ad100.00

Heat the water to about 70° C. and with mixing add the propylene glycoland ethoxydiglycol. Add methylparaben and propylparaben to the heatedsolution and continue to mix until dissolved. Add polysorbate 20 andlauramine oxide with mixing and then clindamycin phosphate, each whilecontinuing to mix the hot solution. In a separate vessel heat octylmethoxycinnamate, Tinosorb® S, cetyl alcohol and stearyl alcohol toabout 70° C. and mix. Add the sunscreen mixture to the clindamycinsolution slowly with vigorous mixing at elevated temperature. Afterformation of a homogeneous blend, mix slowly while cooling to about roomtemperature. Adjust the pH with a 10% solution of sodium hydroxide.

This liquid formulation is packaged into pressurized aerosol containersusing, for example, about 95 parts of the formulation and 5 parts ofaerosol propellant. One suitable aerosol propellant mixture is onecontaining about 85% isobutane and 15% propane.

EXAMPLE 11

The composition of the invention may be formulated as a gel compositioncontaining titanium dioxide as one of the sunscreens as follows and asshown in Table 9.

TABLE 9 Percent COMPONENT (by weight) Clindamycin Phosphate 1.20Titanium Dioxide, micronized 5.00 Edetate Disodium 0.05 Methylparaben0.15 Propylparaben 0.04 Propylene Glycol 10.00 Sodium ThiosulfatePentahydrate 0.16 Hydroxyethyl Cellulose 1.00 Purified Water q.s. ad 100

Dissolve the disodium edetate and the sodium thiosulfate in the waterwith mixing. Then dissolve the clindamycin phosphate in the firstsolution with propeller mixing until add the drug is dissolved. Afterdissolving methylparaben and propylparaben in propylene glycol usingheat as needed up to about 80° C. and propeller mixing, add thissolution slowly while mixing to the clindamycin solution. Add slowly thehydroxyethyl cellulose and disperse it in the clindamycin solution toform a uniform dispersion. Finally add the micronized zinc oxide slowlywith mixing to the gel to complete the formulation.

EXAMPLE 12

The composition of Example 1 was tested in an in vitro model in whichthe sun protection factor (SPF) was estimated to be 14.5. The procedurefor determining the in vitro SPF was as follows. The UV spectralirradiance of a 150 watt xenon arc lamp (Solar Light Company,Philadelphia, Pa.) was measured from 290 to 400 nanometers (nm) using anOL 754 Spectromadiometer with a 6 inch integrating sphere (OptronicLaboratories Incorporated, Orlando, Fla.). Approximately 20 mg of testformulation was applied to a roughened 5 cm×5 cm polymethyl methacrylateplate with a known transmittance spectrum (Wendell et al, SOFW Journal,2001; 127:12-30) and the transmittance spectrum of thesunscreen/substrate combination was measured 5 times at appropriateintervals during irradiation with the solar simulator. The transmittedUV dose was plotted versus the applied UV dose and a least squares curvefit equation was computed for the UV transmission curve (Stanfield, JCosmetic Science, 2001; 52:412-413). One minimal erythemal dose (MED)equals 6.4 effective mJ/cm². The SPF was computed as the cumulativeeffective UV dose applied to the sunscreen/substrate at the time whenthe cumulative transmitted effective UV dose reached 1 MED.

EXAMPLE 13

The composition of Example 2 was tested in an in vitro model in whichthe sun protection factor (SPF) was estimated to be 27.8. The procedurefor determining the in vitro SPF was the same as described in example12.

EXAMPLE 14

The composition of the invention may be formulated as a gel formulationcontaining azelaic acid as the anti-acne agent and two sunscreens asshown in Table 10.

TABLE 10 Percent COMPONENT (by weight) Azelaic Acid 8.00 OctylMethoxycinnamate 4.00 Tinosorb ® S 5.00 Isopropyl Myristate 1.00Propylene Glycol 5.00 Hydroxypropyl Cellulose 2.80 Dehydrated Alcohol,USP q.s. ad 100.00

The azelaic acid sunscreen gel may be made by dissolving the azelaicacid in the alcohol with mixing. Then each of the following ingredientsis added and dissolved with propeller mixing, preferably one at a timeand in the following order: octyl methoxycinnamate, Tinosorb® S,isopropyl myristate, and propylene glycol. Finally, the hydroxypropylcellulose polymer is added slowly with intense mixing to disperse thepolymer followed by side-scrape and countercurrent mixing to make ahomogeneous gel.

Various modifications of the above described invention will be evidentto those skilled in the art. It is intended that such modifications areincluded within the scope of the following claims.

1. A method for increasing the compliance in the use of topicalsunscreens comprising providing to an individual in need thereof aphotostable, chemically stable, and physically stable formulation fortopical application to the skin for treating acne vulgaris andprotecting skin from harmful effects of chronic exposure to the suncomprising a vehicle, one or more sunscreen agents dissolved orsuspended in the vehicle, which sunscreen agent is selected from thegroup consisting of titanium dioxide, zinc oxide, bisoctrizole,anisotriazine, para-aminobenzoic acid (PABA) and derivatives,anthranilates, benzophenones, cinnamates, salicylates, camphorderivatives, benzene 1,4-di(3-methylidene-10-camphosulfonic) acid,drometriazole trisiloxane, and dibenzoylmethanes, and an antibioticmedication that is effective in treating or reducing the signs of acnevulgaris, which antibiotic medication is dissolved or suspended in thevehicle.
 2. The method of claim 1 wherein the sunscreen agent isselected from the group consisting of zinc oxide, titanium oxide,bisoctrizole, and anisotriazine.
 3. The method of claim 1 wherein theformulation contains no sunscreen agent other than those selected fromthe group consisting of titanium dioxide, zinc oxide, bisoctrizole,anisotriazine, para-aminobenzoic acid (PABA), and derivatives,anthranilates, benzophenones, cinnamates, salicylates, camphorderivatives, benzene 1,4-di(3-methylidene-10-camphosulfonic) acid,drometriazole trisiloxane, and dibenzoylmethanes.
 4. The method of claim1 wherein the medication is an antibiotic of the lincomycin family ormacrolide family.
 5. The method of claim 4 wherein the medication is aclindamycin.
 6. The method of claim 1 wherein the formulation furthercomprises an antioxidant.
 7. The method of claim 1 wherein theformulation is free of benzoyl peroxide.
 8. The method of claim 1wherein the vehicle contains one or more of water, alcohol, andpropylene glycol.
 9. The method of claim 1 wherein the formulation isnon-comedogenic.
 10. The method of claim 1 wherein the formulation isfree of emulsifying agents.
 11. The method of claim 1 wherein theformulation is a gel.
 12. The method of claim 11 wherein the formulationcontains a carbomer gelling agent.
 13. The method of claim 4 wherein theformulation further comprises an antioxidant.
 14. The method of claim 5wherein the formulation further comprises an antioxidant.
 15. A methodfor increasing the compliance in the use of topical sunscreenscomprising providing to an individual in need thereof a photostable,chemically stable, and physically stable formulation for topicalapplication to the skin for treating acne vulgaris and protecting skinfrom harmful effects of chronic exposure to the sun comprising avehicle, one or more sunscreen agents dissolved or suspended in thevehicle, which sunscreen agent is selected from the group consisting oftitanium dioxide, zinc oxide, bisoctrizole, anisotriazine, para-aminobenzoic acid (PABA), and derivatives, anthranilates, benzophenones,cinnamates, salicylates, camphor derivatives, benzene1,4-di(3-methylidene-10-camphosulfonic) acid, drometriazole trisiloxane,and dibenzoylmethanes, a clindamycin antibiotic medication which isdissolved or suspended in the vehicle, and an antioxidant.
 16. Themethod of claim 15 wherein the formulation is free of benzoyl peroxide.17. The method of claim 15 wherein the vehicle contains one or more ofwater, alcohol, and propylene glycol.
 18. The method of claim 15 whereinthe formulation is non-comedogenic.
 19. The method of claim 15 whereinthe formulation is free of emulsifying agents.
 20. The method of claim15 wherein the formulation is a gel.
 21. The method of claim 20 whereinthe formulation contains a carbomer gelling agent.